24 research outputs found
Pseudorapidity distributions of charged hadrons in proton-lead collisions at root s(NN)=5:02 and 8.16 TeV
- Author
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- Publication venue
- Publication date
- 01/01/2017
- Field of study
The pseudorapidity distributions of charged hadrons in proton-lead collisions at nucleon-nucleon center-of-mass energies root s(NN) = 5.02 and 8.16 TeV are presented. The measurements are based on data samples collected by the CMS experiment at the LHC. The number of primary charged hadrons produced in non-single-diffractive proton-lead collisions is determined in the pseudorapidity range vertical bar eta(lab)vertical bar vertical bar(vertical bar eta cm vertical bar) <0.5 are 17.1 +/- 0.01 (stat) +/- 0.59 (syst) and 20.10 +/- 0.01 (stat) +/- 0.5(syst) at root s(NN) = 5.02 and 8.16 TeV, respectively. The particle densities per participant nucleon are compared to similar measurements in proton-proton, proton-nucleus, and nucleus-nucleus collisions.Peer reviewe
Whole-genome sequencing reveals host factors underlying critical COVID-19
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- Abd Elghafar M. S.
- Abdel-Aziz M.
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- Wyllie D. H.
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- Zyndorf M.
- Publication venue
- 'Springer Science and Business Media LLC'
- Publication date
- 01/01/2022
- Field of study
Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease
Genetic mechanisms of critical illness in COVID-19.
- Author
- A A Roger Thompson
- A Abraheem
- A Agasou
- A Ahmed
- A Ali
- A Allan
- A Altabaibeh
- A Alvaro
- A Aspinwall
- A Ayers
- A Bamford
- A Barron
- A Bashyal
- A Bellini
- A Bociek
- A Botello
- A Bowes
- A Brady
- A Brayne
- A Brown
- A Brown
- A Butler
- A Campbell
- A Carter
- A Collins
- A Cowley
- A Cowton
- A Cowton
- A Cox
- A Crew
- A Dance
- A Daniel
- A Daniels
- A Dela Rosa
- A Drummond
- A Durie
- A E Heron
- A Easthope
- A Easthope
- A Evans
- A Fofano
- A Gales
- A Ganesan
- A Gardner
- A Garg
- A Gherman
- A Gordon
- A Gratrix
- A Gulati
- A Gupta
- A Haigh
- A Haldeos
- A Harrison
- A Harvey
- A Hayes
- A Higham
- A Higham
- A Hilldrith
- A Holden
- A Hormis
- A Hutcheon
- A Javaid
- A Joseph
- A Kaliappan
- A Katary
- A Kay
- A Kayani
- A Kent
- A Kirkby
- A Knight
- A Kubisz-Pudelko
- A Kuravi
- A Lewis
- A Loveridge
- A Lyle
- A Mayer
- A McAlpine
- A McCarthy
- A McGregor
- A McGregor
- A Meikle
- A Mitchell
- A Mitra
- A Morris
- A Morrison
- A Naranjo
- A Nicholson
- A Nicholson
- A Nilsson
- A Noakes
- A Patel
- A Pickard
- A Poole
- A Price
- A Puxty
- A Quinn
- A Quinn
- A Raithatha
- A Rattray
- A Reddy
- A Reed
- A Reyes
- A Rose
- A Rose
- A Rostron
- A Roy
- A Roynon-Reed
- A S Raj
- A Salberg
- A Sanderson
- A Serrano-Ruiz
- A Solesbury
- A Sukha
- A Swain
- A Tariq
- A Thomas
- A Thomas
- A Todd
- A Tomas
- A Tridente
- A Tucci
- A Turnbull
- A Uriel
- A Ustianowski
- A Vochin
- A Vuylsteke
- A Waite
- A Walden
- A Whileman
- A Wilkinson
- A Williams
- A Williams
- A Wilson
- A Zak
- A Zaki
- Achille Iolascon
- Adam Auton
- Adam Brown
- Agnese Verzuri
- Agostino Ognibene
- Agostino Riva
- Ailsa Golightly
- Alan Maclean
- Alessandra
- Alessandra Stella
- Alessandra Vergori
- Alessia Giorli
- Alexander J Mentzer
- Alice Donati
- Alison M Meynert
- Alistair Nichol
- Ana da Silva Filipe
- Andrea Antinori
- Andrea Cossarizza
- Andrea Ganna
- Andrea Tommasi
- Andrew Rambaut
- Andrew Stenhouse
- Andy Law
- Anjali J Shastri
- Anna Canaccini
- Anna Maria Pinto
- Annarita Giliberti
- Annemarie B Docherty
- Antonella D'Arminio Monforte
- Antonia Ying Wai Ho
- Antonio Di Biagio
- Antony Symons
- Arianna Emiliozzi
- Arianna Gabrieli
- Audrey Coutts
- B Anwar
- B Attwood
- B Baines
- B Blackledge
- B Borislavova
- B Chandler
- B Charles
- B Creagh-Brown
- B David
- B Deacon
- B Deacon
- B Digby
- B Faulkner
- B Fuller
- B Gumbrill
- B Gurung
- B Hadebe
- B Hairsine
- B Hopkins
- B Johnston
- B Lenagh
- B Masunda
- B Ogg
- B Patel
- B Player
- B Purewal
- B Scholefield
- B Shelley
- B Sloan
- B Thomas
- B Wadams
- B Welsh
- B Wilkinson
- B Winter-Goodwin
- B Yates
- Baillie J Kenneth
- Barbara Rossetti
- Beale Rupert
- Beatrice Alex
- Benjamin Bach
- Bretherick Andrew D
- Bruno Frediani
- C Adams
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- C Almaden-Boyle
- C Ashbrook-Raby
- C Basikolo
- C Battle
- C Beazley
- C Beith
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- C Brandwood
- C Brantwood
- C Burnett
- C Castro Delgado
- C Clark
- C Clulow
- C Collins
- C Cruz
- C Davis
- C Demetriou
- C Dennis
- C Dexter
- C Downes
- C Dunmore
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- C Gorman
- C Hays
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- C Holl
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- C Humphrey
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- C Jardine
- C Jennings
- C Jones
- C Kaye
- C Lynch
- C Lyons
- C McCulloch
- C McParland
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- C Murphy
- C Parmar
- C Pawley
- C Phillips
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- C Pothecary
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- C Prendergast
- C Price
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- C Shovelton
- C Sicat
- C Stuart
- C Summers
- C Swan
- C Thompson
- C Thorpe
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- C Vigurs
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- C Whitton
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- C Wrey Brown
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- Carmelo Piscopo
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- Caroline Abernathy
- Carrol Gamble
- Caterina Lo Rizzo
- Catherine A Shaw
- Catherine H Weldon
- Caulfield Mark
- Ceilia Boz
- Cesira Nencioni
- Chelsea Ye
- Chiara Fallerini
- Chiara Gabbi
- Chiara Spertilli
- Chloe Donohue
- Chris Ponting
- Christoper A Green
- Cinthia E Jannes
- Clare Jackson
- Clohisey Sara
- Cristina Mussini
- D Antcliffe
- D Bakthavatsalam
- D Banach
- D Baptista
- D Bell
- D Branney
- D Brealey
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- D Butcher
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- D Cristiano
- D Dawson
- D Donaldson
- D Duffin
- D Fottrell-Gould
- D Golden
- D Griffin
- D Hamilton
- D Hawcutt
- D Hope
- D Horner
- D Kallon
- D Kaye
- D Kelly
- D Loader
- D Lomas
- D Martin
- D McGlynn
- D McLaughlanv
- D Melia
- D Menzies
- D Mullan
- D Pogson
- D Potla
- D Potoczna
- D Purohit
- D Raynard
- D Salutous
- D Salutous
- D Scaletta
- D Shaw
- D Skinner
- D Smyth
- D Strachan
- D Tetla
- D Thornton
- D Trodd
- D Vedage
- D Walker
- D Warren
- D Williams
- D Wood
- D Wright
- Daniela Francisci
- Daniella Coker
- Danilo Tacconi
- David A van Heel
- David Bennet
- David L Robertson
- David Stuart
- Dawn Law
- Debby Bogaert
- Derek Murphy
- Domenico A Coviello
- E Abaleke
- E Allan
- E Anastasescu
- E Andrews
- E Apetri
- E B Jude
- E Beech
- E Beranova
- E Bevan
- E Black
- E Brinkworth
- E Collins
- E Combes
- E Davies
- E Dobson
- E Dooks
- E Fisher
- E Gendall
- E Goff
- E Goodwin
- E Gordon
- E Heeney
- E Horsley
- E Hughes
- E Johnson
- E Knights
- E Lee
- E London
- E Maccacari
- E Massey
- E McKenna
- E Meadows
- E Moncur
- E Morino
- E Mwaura
- E Peasgood
- E Perkins
- E Radford
- E Raith
- E Raith
- E Salciute
- E Smith
- E Smithson
- E Stoddard
- E Stones
- E Thomas
- E Tilney
- E Timlick
- E Treus Gude
- E Virgilio
- E Watson
- E Wilby
- Edoardo Conticini
- Egle Saviciute
- Elena Bargagli
- Elena Desanctis
- Elisa Benetti
- Elisa Frullanti
- Elisabetta Menatti
- Elisabetta Schiaroli
- Ellie Mcmaster
- Emma C Thomson
- Emmanuelle Marques
- Enrico Martinelli
- Esther Duncan
- Esther Merlini
- Ewen M Harrison
- F Anderson
- F Auld
- F Bibi
- F Davies
- F Farquhar
- F Fisher
- F Hurford
- F Kibutu
- F McNeela
- F Moore
- F Nasir
- F Trim
- F Wakinshaw
- F Williams
- Fabio Lena
- Fawkes Angie
- Federico Anedda
- Federico Franchi
- Ferdinando Giannattasio
- Filip Taneski
- Filippo Aucella
- Filippo Biscarini
- Floriana Valentino
- Fourman Max Head
- Francesca Andretta
- Francesca Fava
- Francesca Gatti
- Francesca Mari
- Francesca Montagnani
- Francesco Castelli
- Francesco Raimondi
- Furniss James
- G Andrew
- G Arbane
- G Bell
- G Bercades
- G Croston
- G Debreceni
- G Durrant
- G Hambrook
- G Hobden
- G Houston
- G Hughes
- G Jones
- G Lubimbi
- G Maloney
- G Martir
- G Millen
- G Mills
- G O'Connor
- G Padden
- G Randell
- G Sadera
- G Seddon
- G Sera Howe
- G Sloane
- G Subramanian
- G Tsinaslanidis
- G Turner
- G Watson
- G Wray
- Gabriella Coiro
- Gabriella Doddato
- Gail Carson
- Gardar Sveinbjornsson
- Gary Leeming
- Genni Spargi
- Georgios Pollakis
- Giacomo Zanelli
- Gian Piero Caldarelli
- Giancarlo Bosio
- Giuseppe Fiorentino
- Giuseppe Merla
- Gountouna Elvina
- Graham S Cooke
- Griffiths Fiona
- Grimes Graeme
- H Bancroft
- H Bates
- H Belfield
- H Blackman
- H Blakemore
- H Brooke
- H Button
- H Coles
- H Curgenven
- H Filipe
- H Fox
- H Golding
- H Hill
- H Holcombe
- H Houlden
- H Jeffrey
- H Kent
- H Langton
- H McGuinness
- H Meghari
- H Millward
- H Moore
- H Parker
- H Pearson
- H Prady
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- H Rangarajan
- H Rehman
- H Reschreiter
- H Riley
- H Sainsbury
- H Savill
- H Sturgeon
- H T-Michael
- H Tench
- H Tiveran
- H Turner
- H Whittle
- H Willis
- H Wood
- Haley Chris
- Hanning Mal
- Harrison David
- Hayley Hardwick
- Hayward Caroline
- Helen Szoor-McElhinney
- Hinds Charles
- Ho Antonia
- Horby Peter
- I Ali Mohamed Ali
- I Balagosa
- I Birkinshaw
- I Burn
- I Chadbourn
- I D Clement
- I Edmond
- I Frost
- I Hass
- I Hussain
- I Lancoma-Malcolm
- I Leadbitter
- I Nagra
- I Otahal
- I Otahal
- I Turner-Bone
- I Welters
- I White
- I Wynter
- Ilaria Meloni
- Immacolata Andolfo
- Isabella Zanella
- J Allan
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- J Bewley
- J Biddle
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- J Camsooksai
- J Carter
- J Caterson
- J Cebrian Suarez
- J Cockerill-Taylor
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- J Egan
- J Fernandez Roman
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- J Jones
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- Jorge Esparza-Gordillo
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- Stefano Rusconi
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- Stephanie Roberts
- Stephen R Knight
- Summers Charlotte
- Susanna Croci
- Susanna Guerrini
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- Teresa Filshtein-Sonmez
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- Thushan de Silva
- Tim Walsh
- Tom Fletcher
- Tom Solomon
- Tony Wackett
- Trevor Paterson
- Tullio Trotta
- Turtle Lance
- U Poultney
- V Amin
- V Anumakonda
- V Bastion
- V Cannons
- V Crickmore
- V Gopal
- V Irvine
- V Kasipandian
- V Krishnamurthy
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- V Linnett
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- Vanessa Sancho-Shimizu
- Victoria Shaw
- Vitart Veronique
- W Harrison
- W Khaliq
- W Khaliq
- W McCormick
- W Woodyatt
- Walker Susan
- Walsh Timothy
- Wang Bo
- Wei Shen Lim
- Wendy S Barclay
- William A Paxton
- William Greenhalf
- Wilson James F
- Wrobel Nicola
- Wu Yang
- X Qiu
- Y Baird
- Y Choudhury
- Y Hussain
- Y Jackson
- Y Thirlwall
- Yang Jian
- Yang Zhijian
- Z Alldis
- Z Belagodu
- Z Bradshaw
- Z Coton
- Z Daly
- Z Farzad
- Z Fernandez
- Z Garland
- Z Maqsood
- Z Omar
- Z Prime
- Z Scott
- Zechner Marie
- Zhai Ranran
- Zheng Chenqing
- Publication venue
- Nature
- Publication date
- 01/01/2020
- Field of study
Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 × 10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice
First low-frequency Einstein@Home all-sky search for continuous gravitational waves in Advanced LIGO data
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- Publication venue
- 'American Physical Society (APS)'
- Publication date
- 01/01/2017
- Field of study
We report results of a deep all-sky search for periodic gravitational waves from isolated neutron stars in data from the first Advanced LIGO observing run. This search investigates the low frequency range of Advanced LIGO data, between 20 and 100 Hz, much of which was not explored in initial LIGO. The search was made possible by the computing power provided by the volunteers of the Einstein@Home project. We find no significant signal candidate and set the most stringent upper limits to date on the amplitude of gravitational wave signals from the target population, corresponding to a sensitivity depth of 48.7 [1/root Hz]. At the frequency of best strain sensitivity, near 100 Hz, we set 90% confidence upper limits of 1.8 x 10(-25). At the low end of our frequency range, 20 Hz, we achieve upper limits of 3.9 x 10(-24). At 55 Hz we can exclude sources with ellipticities greater than 10(-5) within 100 pc of Earth with fiducial value of the principal moment of inertia of 10(38) kg m(2)
Search for intermediate mass black hole binaries in the first observing run of Advanced LIGO
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- Zweizig J.
- Publication venue
- 'American Physical Society (APS)'
- Publication date
- 01/01/2017
- Field of study
During their first observational run, the two Advanced LIGO detectors attained an unprecedented sensitivity, resulting in the first direct detections of gravitational-wave signals produced by stellar-mass binary black hole systems. This paper reports on an all-sky search for gravitational waves (GWs) from merging intermediate mass black hole binaries (IMBHBs). The combined results from two independent search techniques were used in this study: the first employs a matched-filter algorithm that uses a bank of filters covering the GW signal parameter space, while the second is a generic search for GW transients (bursts). No GWs from IMBHBs were detected; therefore, we constrain the rate of several classes of IMBHB mergers. The most stringent limit is obtained for black holes of individual mass
100 M ⊙, with spins aligned with the binary orbital angular momentum. For such systems, the merger rate is constrained to be less than
0.93 Gpc−3yr−1 in comoving units at the 90% confidence level, an improvement of nearly 2 orders of magnitude over previous upper limits
Whole-genome sequencing reveals host factors underlying critical COVID-19
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- Abd Elghafar M.S.
- Abdel-Aziz M.
- Abdelrazik M.
- Abdollahi H.
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- Zyndorf M.
- Zöllner S.
- Åsvold B.O.
- Publication venue
- Springer Science and Business Media LLC
- Publication date
- 07/07/2022
- Field of study
Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease
31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two
- Author
- Abassi Yama
- Abelin Jennifer G
- Abolhalaj Milad
- Abraham Tara S
- Adam Ammar
- Adams David
- Adams Homer
- Adams Sarah F
- Adamus Tomasz
- Addepalli Murali
- Addepalli Murali
- Adjei Alex A
- Agapova Larissa
- Agarwala Sanjiv
- Ager Casey
- Aggarwal Charu
- Agnello Giulia
- Agudo Judith
- Aguilar Ethan G
- Aguilera Todd
- Ahamadi Malidi
- Ahn Yong-Oon
- Ahrens Eric T
- Aizer Ayal
- Ajina Reham
- Akerley Wallace
- Al-Muftah Mariam
- Albershardt Tina C
- Albershardt Tina C
- Albrekt Ann-Sofie
- Alekar Shilpa
- Alemany Ramon
- Alemany Ramon
- Alexander Brian
- Allbritton Omaira
- Allen Clint T
- Alley Evan W
- Allison James
- Allison James
- Allison James
- Alston Tesha
- Alt Jürgen
- Alters Susan
- Amatulli Michael
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- Ye Yun-bin
- Yin Catherine
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- Ylösmäki Erkko
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- Young Steve W
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- Yu Huakui
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- Zafar Sadia
- Zalevsky Jonathan
- Zalevsky Jonathan
- Zalevsky Jonathan
- Zalevsky Jonathan
- Zappasodi Roberta
- Zappasodi Roberta
- Zauderer Maurice
- Zeh Herbert
- Zelenetz Andrew D
- Zeng Weiping
- Zeng Xue
- Zha Yuanyuan
- Zhang Danhui
- Zhang Jing
- Zhang Ping
- Zhang Qifang
- Zhang Shannon S
- Zhang Theresa
- Zhang Winter
- Zhang Yanping
- Zhao Fei
- Zhao Leyna
- Zhao Xingli
- Zheng Lianxing
- Zheng Wenxin
- Zheng Xianxian
- Zheng Yi
- Zhong Hong
- Zhou Li
- Zhou Xiangjun
- Zippelius Alfred
- Zloza Andrew
- Zloza Andrew
- Zloza Andrew
- Zloza Andrew
- Zloza Andrew
- Zou Jun
- Zuba-Surma Ewa
- Zubkova Olga
- Zureikat Amer
- Publication venue
- 'Springer Science and Business Media LLC'
- Publication date
- 01/01/2016
- Field of study
Background
The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd.
Methods
We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background.
Results
First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001).
Conclusions
In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival
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- Aali Amirali
- Ababneh Hazim S
- Abate Yohannes Habtegiorgis
- Abbafati Cristiana
- Abbasgholizadeh Rouzbeh
- Abbasi-Kangevari Mohsen
- Abbasian Mohammadreza
- Abbastabar Hedayat
- Abd ElHafeez Samar
- Abd-Elsalam Sherief
- Abdelmasseh Michael
- Abdelwahab Ahmed
- Abdollahi Mohammad
- Abdollahifar Mohammad-Amin
- Abdoun Meriem
- Abdulah Deldar Morad
- Abdullahi Auwal
- Abebe Mesfin
- Abebe Samrawit Shawel
- Abedi Aidin
- Abegaz Kedir Hussein
- Abhilash E S
- Abidi Hassan
- Abiodun Olumide
- Aboagye Richard Gyan
- Abolhassani Hassan
- Abolmaali Meysam
- Abouzid Mohamed
- Aboye Girma Beressa
- Abreu Lucas Guimarães
- Abrha Woldu Aberhe
- Abtahi Dariush
- Abu Rumeileh Samir
- Abu-Gharbieh Eman
- Abu-Rmeileh Niveen ME
- Abu-Zaid Ahmed
- Abualruz Hasan
- Abubakar Bilyaminu
- Aburuz Salahdein
- Accrombessi Manfred Mario Kokou
- Adal Tadele Girum
- Adamu Abdu A
- Addo Isaac Yeboah
- Addolorato Giovanni
- Adebiyi Akindele Olupelumi
- Adekanmbi Victor
- Adepoju Abiola Victor
- Adetunji Charles Oluwaseun
- Adetunji Juliana Bunmi
- Adeyeoluwa Temitayo Esther
- Adeyinka Daniel Adedayo
- Adeyomoye Olorunsola Israel
- Admass Biruk Adie Adie
- Adnani Qorinah Estiningtyas Sakilah
- Adra Saryia
- Afolabi Aanuoluwapo Adeyimika
- Afzal Muhammad Sohail
- Afzal Saira
- Agampodi Suneth Buddhika
- Agasthi Pradyumna
- Aggarwal Manik
- Aghamiri Shahin
- Agide Feleke Doyore
- Agodi Antonella
- Agrawal Anurag
- Agyemang-Duah Williams
- Ahinkorah Bright Opoku
- Ahmad Aqeel
- Ahmad Danish
- Ahmad Firdos
- Ahmad Muayyad M
- Ahmad Sajjad
- Ahmad Shahzaib
- Ahmad Tauseef
- Ahmadi Keivan
- Ahmadzade Amir Mahmoud
- Ahmed Ali
- Ahmed Ayman
- Ahmed Haroon
- Ahmed Luai A
- Ahmed Mehrunnisha Sharif
- Ahmed Meqdad Saleh
- Ahmed Muktar Beshir
- Ahmed Syed Anees
- Ajami Marjan
- Aji Budi
- Akara Essona Matatom
- Akbarialiabad Hossein
- Akinosoglou Karolina
- Akinyemiju Tomi
- Akkaif Mohammed Ahmed
- Akyirem Samuel
- Al Hamad Hanadi
- Al Hasan Syed Mahfuz
- Al-Aly Ziyad
- Al-amer Rasmieh Mustafa
- Al-Azzam Sayer
- Al-Gheethi Adel Ali Saeed
- Al-Hanawi Mohammed Khaled
- Al-Marwani Sabah
- Al-Maweri Sadeq Ali Ali
- Al-Mekhlafi Hesham M
- Al-Omari Basem
- Al-Sabah Salman Khalifah
- Al-Tawfiq Jaffar A
- Al-Worafi Yaser Mohammed
- Alahdab Fares
- Alalalmeh Samer O
- Alalwan Tariq A
- Alam Khurshid
- Alam Manjurul
- Alam Noore
- Alanezi Fahad Mashhour
- Alanzi Turki M
- Albakri Almaza
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- AlBataineh Mohammad T
- Alcalde-Rabanal Jacqueline Elizabeth
- Aldawsari Khalifah A
- Aldhaleei Wafa A
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- Alema Haileselasie Berhane
- Alemayohu Mulubirhan Assefa
- Alemi Sharifullah
- Alemu Yihun Mulugeta
- Alhabib Khalid F
- Alhalaiqa Fadwa Alhalaiqa Naji
- Ali Abid
- Ali Amjad
- Ali Liaqat
- Ali Mohammed Usman
- Ali Rafat
- Ali Shahid
- Ali Syed Shujait Shujait
- Alicandro Gianfranco
- Alif Sheikh Mohammad
- Alikhani Reyhaneh
- Alimohamadi Yousef
- Aliyi Ahmednur Adem
- Aljasir Mohammad A M
- Aljunid Syed Mohamed
- Alla François
- Allebeck Peter
- Almazan Joseph Uy
- Almidani Louay
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- Alqalyoobi Shehabaldin
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- Amirzade-Iranaq Mohammad Hosein
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- Amugsi Dickson A
- Amusa Ganiyu Adeniyi
- Ancuceanu Robert
- Anderlini Deanna
- Anderson David B
- Andrade Pedro Prata
- Andrei Catalina Liliana
- Andrei Tudorel
- Angus Colin
- Anil Abhishek
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- Ansari Hossein
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- Ansariadi Ansariadi
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- Antriyandarti Ernoiz
- Anvari Davood
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- Anwer Razique
- Anyasodor Anayochukwu Edward
- Aqeel Muhammad
- Arab Juan Pablo
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- Aravkin Aleksandr Y
- Areda Demelash
- Aremu Abdulfatai
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- Arkew Mesay
- Armocida Benedetta
- Arndt Michael Benjamin
- Arooj Mahwish
- Artamonov Anton A
- Arulappan Judie
- Aruleba Raphael Taiwo
- Arumugam Ashokan
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- Atlaw Habtamu Wondmagegn
- Atorkey Prince
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- Ausloos Marcel
- Avan Abolfazl
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- Aweke Amlaku Mulat
- Ayala Quintanilla Beatriz Paulina
- Ayatollahi Haleh
- Ayuso-Mateos Jose L
- Ayyoubzadeh Seyed Mohammad
- Azadnajafabad Sina
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- B Darshan B
- Babu Abraham Samuel
- Badar Muhammad
- Badiye Ashish D
- Baghdadi Soroush
- Bagheri Nasser
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- Bah Sulaiman
- Bahadorikhalili Saeed
- Bahmanziari Najmeh
- Bai Ruhai
- Baig Atif Amin
- Baker Jennifer L
- Bako Abdulaziz T
- Bakshi Ravleen Kaur
- Balakrishnan Senthilkumar
- Balasubramanian Madhan
- Baltatu Ovidiu Constantin
- Bam Kiran
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- Banik Palash Chandra
- Bansal Hansi
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- Bardhan Mainak
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- Barker-Collo Suzanne Lyn
- Barone-Adesi Francesco
- Barqawi Hiba Jawdat
- Barrero Lope H
- Barrow Amadou
- Barteit Sandra
- Barua Lingkan
- Basharat Zarrin
- Bashiri Azadeh
- Basiru Afisu
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- Bassat Quique
- Basso João Diogo
- Basting Ann V L
- Basu Sanjay
- Batra Kavita
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- Bayileyegn Nebiyou Simegnew
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- Belay Sefealem Assefa
- Belete Chalie Mulu
- Bell Michelle L
- Bello Muhammad Bashir
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- Beloukas Apostolos
- Bender Rose Grace
- Bensenor Isabela M
- Beran Azizullah
- Berezvai Zombor
- Berhie Alemshet Yirga
- Berice Betyna N
- Bernstein Robert S
- Bertolacci Gregory J
- Bettencourt Paulo J G
- Beyene Kebede A
- Bhagat Devidas S
- Bhagavathula Akshaya Srikanth
- Bhala Neeraj
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- Momtazmanesh Sara
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- Yamagishi Kazumasa
- Yang Danting
- Yang Lin
- Yano Yuichiro
- Yao Yao
- Yaribeygi Habib
- Ye Pengpeng
- Yehualashet Sisay Shewasinad
- Yesiltepe Metin
- Yesuf Subah Abderehim
- Yezli Saber
- Yi Siyan
- Yigezu Amanuel
- Yip Paul
- Yismaw Malede Berihun
- Yismaw Yazachew
- Yiğit Arzu
- Yiğit Vahit
- Yon Dong Keon
- Yonemoto Naohiro
- Yoon Seok-Jun
- You Yuyi
- Younis Mustafa Z
- Yousefi Zabihollah
- Yu Chuanhua
- Yu Yong
- Yuh Faith H
- Zadey Siddhesh
- Zadnik Vesna
- Zafari Nima
- Zakham Fathiah
- Zaki Nazar
- Zaman Sojib Bin
- Zamora Nelson
- Zand Ramin
- Zangiabadian Moein
- Zar Heather J
- Zare Iman
- Zarrintan Armin
- Zeariya Mohammed G M
- Zeinali Zahra
- Zhang Haijun
- Zhang Jianrong
- Zhang Jingya
- Zhang Liqun
- Zhang Yunquan
- Zhang Zhi-Jiang
- Zhao Hanqing
- Zhong Chenwen
- Zhou Juexiao
- Zhu Bin
- Zhu Lei
- Ziafati Makan
- Zielińska Magdalena
- Zitoun Osama A
- Zoladl Mohammad
- Zou Zhiyong
- Zuhlke Liesl J
- Zumla Alimuddin
- Zweck Elric
- Zyoud Samer H
- Ärnlöv Johan
- Šekerija Mario
- Publication venue
- Elsevier
- Publication date
- 03/04/2024
- Field of study
BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation
Drug-induced anomalous contraction of gastrointestinal tract of mice with impaired c-kit function.
- Author
- Isozaki K Hirota S, Miyagawa J, Ta
- Kubota M Ito Y, Ikeda K
- Lagaud G Karicheti V, Knot HJ, Chr
- Langton P Ward SM, Carl A, Norell
- Lin Z Forster J, Sarosiek I, McCal
- NAKAYAMA S
- Pestronk A Drachman DB
- Qiu F. Ray P., Brown K., Barker P.
- Russell ES
- Sato D Lai ZF, Tokutomi N, et al
- SUZUKI H
- Thuneberg L Rumessen JJ, Mikkelsen
- Tokutomi N Maeda H, Tokutomi Y, et
- Vanderwinden JM Liu H, De Laet MH,
- Ward SM Burns AJ, Torihashi S, San
- Yarden Y., Kuang, W.J., Yang-Feng,
- 高山一郎 醍醐弥太郎,小嶋裕一郎,藤野雅之
- Publication venue
- 'Japanese Pharmacological Society'
- Publication date
- 01/01/2004
- Field of study